Dopamine receptor agonists are important agents for the treatment of Parkinson Disease. At present, clinically used dopamine receptor agonists include dopaminic agonists such as rotigotine, pramipexole, ropinirole, pergolide, terguride, quinagolide, cabergoline and their derivatives and pharmaceutically acceptable salts, and those under clinical trails include sumanirole, SLV-308, adrogolide, ABT-431, Dinapsoline, BAM-1110 and their derivatives and pharmaceutically acceptable salts.
The above medicines usually are administrated orally or transdermally in clinic. Although the oral administration is convenient, patients under advanced Parkinson Disease usually have failure of memory and may forget to take medicines, which will deteriorate their conditions. In addition, the relatively great fluctuation of drug concentration after oral administration may aggravate side-effects and result in “on-off phenomenon”, and gastrointestinal tract and liver first pass effect reduce the bioavailability. For example, the bioavailability of rotigotine for oral administration is only 1-5% due to the first pass effect in liver, so that oral dosage forms are not suitable. On the other hand, the transdermal absorption of normal transdermal dosage forms such as ointments, plasters, etc. is not sufficient and often varies because the transdermal absorption is affected by many factors. In addition, transdermal dosage forms are affected by low permeability of skin and thus have low intake, low bioavailability and great individual difference, so that their therapeutic effects are limited, especially for advanced Parkinson Disease patients.
Parenteral administration such as injection can avoid first pass effect, but rotigotine and pramipexole, etc. have a short half-life of only a couple of hours and thus should be administrated several times per day, and other drugs with a relatively longer half-life still should be administrated daily or bidaily and hardly facilitate the administration for patients with Parkinson Disease.
Thus, it is expected to provide a long-acting sustained-release dosage form of dopamine receptor agonist, which is preferably not orally administrated, but intramuscularly injected or subcutaneously administrated, and which can maintain a stable release rate for several weeks, several months or longer so as to reduce as much as possible the pain of patients with Parkinson Disease.
CN1531428A (WO2002/015903) disclosed a Depot-form type sustained-release preparation of rotigotine, wherein the use of a so-called “depot” obtained by suspending rotigotine hydrochloride in an oilly solvent extended the administration interval to more than one day. Although CN1531428A cites the prior art EP0625069 (CN1090172A) which mentioned the preparation of microparticles or micro-capsules (i.e., the microspheres of the present invention) of rotigotine for the implementation of sustained-release, it discloses nothing about the components of micro-capsules or sustained-release microspheres of rotigotine and proportions thereof.
To achieve a long-acting sustained-release preparation that have a administration interval of once weekly or bi-weekly, even once monthly or longer, not only the sustained-release dosage form should stably release drug in vivo for a long period in order to maintain an effective blood drug level in vivo during the period, but also the dosage form should not cause significant side-effects after it is injected into the body, Thus, the use and amounts of both the active component and accessories should be strictly defined in order to implement the administration interval of one or more weeks, even one month and to achieve better therapeutic effects.
CN1531428A and CN1090172A disclose nothing about the sustained-release dosage forms of dopamine receptor agonists and accessories thereof, so that long-acting sustained-release dosage forms (having an administration interval of one or two weeks, even one month or more) of dopamine receptor agonists including rotigotine are actually still unknown.
The inventors of the present invention conducted deep researches for implementation of the long-acting sustained-release of dopamine receptor agonists, and discovered that injectable sustained-release microspheres, implants and injectable gels obtained by using a biodegradable polymer to embed an active component could continuously, stably release the active component for several weeks even several months after they are administrated intramuscularly or subcutaneously, and in the meantime they had high bioavailability, small fluctuation of blood drug level and greatly reduced administration frequency. As compared with traditional oral dosage forms, the side-effects were reduced, the frequency of occurrence of “on-off phenomena” decreased, in the meantime the bioavailability increased significantly, the compliance of patients were improved, and the therapeutic effects of these medicines were achieved to the fullest extent. On this basis, the present invention is carried out.